Renal function alters the association of lipoprotein(a) with cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a prospective cohort study.

Background and hypothesis: Lipoprotein(a) [Lp(a)] and renal dysfunction are both independent risk factors for cardiovascular disease. However, it remains unclear whether renal function mediates the association between Lp(a) and cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI). Methods: From a large prospective cohort study, 10 435 eligible patients undergoing PCI from January 2013 to December 2013 were included in our analysis. Patients were stratified into three renal function groups according to their baseline estimated glomerular filtration rate (eGFR) (<60; 60-90; ≥90 ml/min/1.73 m2). The primary endpoint was a composite of all-cause death, nonfatal MI, ischemic stroke, and unplanned revascularization [major adverse cardiac and cerebrovascular events (MACCE)]. Results: Over a median follow-up of 5.1 years, a total of 2144 MACCE events occurred. After multivariable adjustment, either eGFR <60 ml/min/1.73 m2 or elevated Lp(a) conferred a significantly higher MACCE risk. Higher Lp(a) was significantly associated with an increased risk of MACCE in patients with eGFR <60 ml/min/1.73 m2. However, this association was weakened in subjects with only mild renal impairment and diminished in those with normal renal function. A significant interaction for MACCE between renal categories and Lp(a) was observed (P = 0.026). Patients with concomitant Lp(a) ≥30 mg/dl and eGFR <60 ml/min/1.73 m2 experienced worse cardiovascular outcomes compared with those without. Conclusion: The significant association between Lp(a) and cardiovascular outcomes was mediated by renal function in patients undergoing PCI. Lp(a)-associated risk was more pronounced in patients with worse renal function, suggesting close monitoring and aggressive management are needed in this population.

Prolonging dual antiplatelet therapy improves the long-term prognosis in patients with diabetes mellitus undergoing complex percutaneous coronary intervention.

OBJECTIVE: To investigate the optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) requiring complex percutaneous coronary intervention (PCI). METHODS: A total of 2403 patients with DM who underwent complex PCI from January to December 2013 were consecutively enrolled in this observational cohort study and divided according to DAPT duration into a standard group (11-13 months, n = 689) and two prolonged groups (13-24 months, n = 1133; > 24 months, n = 581). RESULTS: Baseline characteristics, angiographic findings, and complexity of PCI were comparable regardless of DAPT duration. The incidence of major adverse cardiac and cerebrovascular event was lower when DAPT was 13-24 months than when it was 11-13 months or > 24 months (4.6% vs. 8.1% vs. 6.0%, P = 0.008), as was the incidence of all-cause death (1.9% vs. 4.6% vs. 2.2%, P = 0.002) and cardiac death (1.0% vs. 3.0% vs. 1.2%, P = 0.002). After adjustment for confounders, DAPT for 13-24 months was associated with a lower risk of major adverse cardiac and cerebrovascular event [hazard ratio (HR) = 0.544, 95% CI: 0.373-0.795] and all-cause death (HR = 0.605, 95% CI: 0.387-0.944). DAPT for > 24 months was associated with a lower risk of all-cause death (HR = 0.681, 95% CI: 0.493-0.942) and cardiac death (HR = 0.620, 95% CI: 0.403-0.952). The risk of major bleeding was not increased by prolonging DAPT to 13-24 months (HR = 1.356, 95% CI: 0.766-2.401) or > 24 months (HR = 0.967, 95% CI: 0.682-1.371). CONCLUSIONS: For patients with DM undergoing complex PCI, prolonging DAPT might improve the long-term prognosis by reducing the risk of adverse ischemic events without increasing the bleeding risk.

Association between cumulative lipoprotein(a) exposure and adverse cardiovascular outcomes in patients with prediabetes or diabetes.

Few studies have characterized long-term exposure to lipoprotein(a), or Lp(a), different glucose metabolism status, and their joint role in adverse cardiovascular outcomes risk. We consecutively enrolled 10,724 coronary heart disease (CAD) patients from January to December 2013 in Fuwai Hospital. Associations of cumulative lipoprotein(a) (CumLp(a)) exposure and different glucose metabolism status with major adverse cardiac and cerebrovascular events (MACCEs) risk were evaluated using Cox regression models. Compared with participants with normal glucose regulation and lower CumLp(a), those with type 2 diabetes and higher CumLp(a) were at the highest risk (HR 1.56, 95% CI 1.25-1.94), and those with prediabetes and higher CumLp(a) and those with type 2 diabetes and lower CumLp(a) were at relatively higher risk (HR 1.41, 95% CI 1.14-1.76; HR 1.37, 95% CI 1.11-1.69; respectively). Similar findings concerning the joint association were observed in sensitivity analyses. Cumulative lipoprotein(a) exposure and different glucose metabolism status were associated with 5-year MACCEs risk and may be useful concurrently for guiding secondary prevention therapy decisions.

Upscaling dispersivity for conservative solute transport in naturally fractured media.

Physical heterogeneities are prevalent features of fracture systems and significantly impact transport processes in aquifers across different spatiotemporal scales. Upscaling solute transport parameter is an effective way of quantifying parameter variability in heterogeneous aquifers including fractured media. This paper develops conceptual models for upscaling conservative transport parameters in fracture media. The focus is on upscaling dispersivity. Lagrangian-based transport model (LBTM) for dispersivity upscaling are derived for the solute transport in two-dimensional fractures surrounded by an impermeable matrix. The LBTM is validated against the random walk particle tracking (RWPT) model, which enables highly efficient and accurate predictions of conservative solute transport. The results show that the derived scale-dependent analytical expressions are in excellent agreement with RWPT model results. In addition, LBTM results are also compared to experimental results from the observed breakthrough curve of a conservative solute transport through a single natural fracture within a granite core. Comparing results from the LBTM and transport experiment shows that LBTM based estimated dispersivity is 10.55% higher than the measured value. Errors introduced by the experiments, the conceptual assumptions in deriving models, and the heterogeneities of fracture apertures not fully sampled by measuring instruments are main factor for such discrepancy. The sensitivity analysis indicates that the longitudinal and transverse dispersivities are positively related to the integral scale and the variance of the log-fracture aperture. The longitudinal dispersivity is strongly contolled by the variance of the log-fracture aperture. The LBTM may be useful for directly predicting solute transports, requiring only the acquisition of fractured geostatistical data. This work provides a better understanding of transport processes in fractured media which ultimately control water quality across scales.

Association of prognostic nutritional index level and diabetes status with the prognosis of coronary artery disease: a cohort study.

BACKGROUND: Malnutrition and inflammation are associated with adverse clinical outcomes in patients with diabetes or coronary artery disease (CAD). Prognostic nutritional index (PNI) is a comprehensive and simple indicator reflecting nutritional condition and immunological status. Whether there is a crosstalk between nutritional-immunological status and diabetes status for the impact on the prognosis of coronary artery disease (CAD) is unclear. METHODS: A total of 9429 consecutive CAD patients undergoing percutaneous coronary intervention were grouped by diabetes status [diabetes (DM) and non-diabetes (non-DM)] and preprocedural PNI level [high PNI (H-PNI) and low PNI (L-PNI)] categorized by the statistically optimal cut-off value of 48.49. The primary endpoint was all-cause death. RESULTS: During a median follow-up of 5.1 years (interquartile range: 5.0-5.1 years), 366 patients died. Compared with the non-DM/H-PNI group, the DM/L-PNI group yielded the highest risk of all-cause death (adjusted hazard ratio: 2.65, 95% confidence interval: 1.97-3.56, p < 0.001), followed by the non-DM/L-PNI group (adjusted hazard ratio: 1.44, 95% confidence interval: 1.05-1.98, p = 0.026), while DM/H-PNI was not associated with the risk of all-cause death. The negative effect of L-PNI on all-cause death was significantly stronger in diabetic patients than in nondiabetic patients (p for interaction = 0.037). Preprocedural PNI category significantly improved the Global Registry of Acute Coronary Events (GRACE) risk score for predicting all-cause death in patients with acute coronary syndrome, especially in those with diabetes. CONCLUSIONS: CAD patients with diabetes and L-PNI experienced the worst prognosis. The presence of diabetes amplifies the negative effect of L-PNI on all-cause death. Poor nutritional-immunological status outweighs diabetes in increasing the risk of all-cause death in CAD patients. Preprocedural PNI can serve as an assessment tool for nutritional and inflammatory risk and an independent prognostic factor in CAD patients, especially in those with diabetes.

Prolonged dual antiplatelet therapy after drug-eluting stent implantation improves long-term prognosis for acute coronary syndrome: five-year results from a large cohort study.

BACKGROUND: To investigate the most appropriate dual antiplatelet therapy (DAPT) duration for patients with acute coronary syndrome (ACS) after drug-eluting stent (DES) implantation in the largest cardiovascular center of China. METHODS: We enrolled 5,187 consecutive patients with ACS who received DES from January to December 2013. Patients were divided into four groups based on DAPT duration: standard DAPT group (11-13 months, n=1,568) and prolonged DAPT groups (13-18 months [n=308], 18-24 months [n=2,125], and >24 months [n=1,186]). Baseline characteristics and 5-year clinical outcomes were recorded. RESULTS: Baseline characteristics were similar across the four groups. Among the four groups, those with prolonged DAPT (18-24 months) had the lowest incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) (14.1% vs. 11.7% vs. 9.6% vs. 24.2%, P<0.001), all-cause death (4.8% vs. 3.9% vs. 2.1% vs. 2.6%, P<0.001), cardiac death (3.1% vs. 2.6% vs. 1.4% vs. 1.9%, P=0.004), and myocardial infarction (MI) (3.8% vs. 4.2% vs. 2.5% vs. 5.8%, P<0.001). The incidence of bleeding was not different among the four groups (9.9% vs. 9.4% vs. 11.0% vs. 9.4%, P=0.449). Cox multivariable analysis showed that prolonged DAPT (18-24 months) was an independent protective factor for MACCEs (hazard ratio [HR] 0.802, 95% confidence interval [CI] 0.729-0.882, P<0.001), all-cause death (HR 0.660, 95% CI 0.547-0.795, P<0.001), cardiac death (HR 0.663, 95% CI 0.526-0.835, P<0.001), MI (HR 0.796, 95% CI 0.662-0.957, P=0.015), and target vessel revascularization (HR 0.867, 95% CI 0.755-0.996, P=0.044). Subgroup analysis for high bleeding risk showed that prolonged DAPT remained an independent protective factor for all-cause death and MACCEs. CONCLUSION: For patients with ACS after DES, appropriately prolonging the DAPT duration may be associated with a reduced risk of adverse ischemic events without increasing the bleeding risk.

The human health risk assessment and countermeasures study of groundwater quality.

Due to various geological, hydrogeological conditions and human activities, groundwater of different regions has distinct hydrochemical characteristics. The harmful chemical components of groundwater affect human health, and thus, the groundwater quality health risk assessment (GQHR) is important to local residents. It is vital to select GQHR factors combined with hydrochemical features, and to explore their formation, concentration characteristics and the prominent controlling role of influencing risk distribution from natural and human reasons. The factors of NO3-, NO2-, NH4+ and F- were extracted as assessment factors to evaluate the GQHR. The factors NO3-, NO2- and NH4+ are derived by human activities and F- stems from irrigation of geogenic high-fluoride groundwater and fertilizer use. The results of GQHR showed the risk order as children > adult females > adult males. The low- and medium-risk regions correspond to high groundwater levels, which are mainly controlled by natural factors. The high-risk regions located in eastern part of the study area, which were affected by both natural and human reasons. The targeted measures to prevent the increase of groundwater health risk caused by different dominant controlling effects were put forward. The research provides a scientific basis for the safety of groundwater supply and environmental exposure in this area. The research ideas and methods can be a reference for similar studies.

Associations of lipid measures with total occlusion in patients with established coronary artery disease: a cross-sectional study.

BACKGROUND: Total occlusion is the most severe coronary lesion, indicating heavy ischemic burden and poor prognosis. The lipid profile is central to the development of atherosclerotic coronary lesions. Evidence on the optimal lipid measure to be monitored and managed in patients with established coronary artery disease (CAD) is inconclusive. METHODS: Total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), nonhigh-density lipoprotein cholesterol (non-HDL-c), lipoprotein (a) [Lp(a)], apolipoprotein B (apoB), non-HDL-c/HDL-c, and apoB/apoA-1 were analyzed in quintiles and as continuous variables. The associations of lipid measures with total occlusion were tested using logistic regression models, visualized with restricted cubic splines, and compared by areas under the receiver operating characteristic curves (AUROC). Discordance analysis was performed when apoB/apoA-1 and non-HDL-c/HDL-c were not in concordance. RESULTS: The prospective cohort study included 10,003 patients (mean age: 58 years; women: 22.96%), with 1879 patients having total occlusion. The risks of total occlusion significantly increased with quintiles of Lp(a), non-HDL-c/HDL-c, and apoB/apoA-1 (all p for trend < 0.001). TG had no association with total occlusion. Restricted cubic splines indicate significant positive linear relations between the two ratios and total occlusion [odds ratio per 1-standard deviation increase (95% confidence interval): non-HDL-c/HDL-c: 1.135 (1.095-1.176), p < 0.001; apoB/apoA-1: 2.590 (2.049-3.274), p < 0.001]. The AUROCs of apoB/apoA-1 and non-HDL-c/HDL-c were significantly greater than those of single lipid measures. Elevation in the apoB/apoA-1 tertile significantly increased the risk of total occlusion at a given non-HDL-c/HDL-c tertile but not vice versa. CONCLUSION: ApoB/apoA-1 confers better predictive power for total occlusion than non-HDL-c/HDL-c and single lipid measures in established CAD patients.

Lipoprotein(a), high-sensitivity C-reactive protein, and cardiovascular risk in patients undergoing percutaneous coronary intervention.

BACKGROUND AND AIMS: In patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), the effects of high-sensitivity C-reactive protein (hsCRP) on Lipoprotein(a) (Lp(a))-associated cardiovascular risk remains unclear. This study aimed to investigate the independent and combined association of Lp(a) and hsCRP with cardiovascular events in this specific population. METHODS: A total of 10,424 patients with measurements of both Lp(a) and hsCRP were included in this prospective cohort study. Cox proportional hazards models and Kaplan-Meier analysis were performed to evaluate the relationship between Lp(a), hsCRP and adverse cardiac and cerebrovascular events (MACCE; all-cause death, myocardial infarction, ischemic stroke and revascularization). RESULTS: During 5 years of follow-up, 2140 (20.5%) MACCE occurred. Elevated Lp(a) and hsCRP levels were associated with increased risks of MACCE (p<0.05). Notably, there might be a significant interaction between Lp(a) and hsCRP (P for interaction = 0.019). In the setting of hsCRP≥2 mg/L, significant higher risk of MACCE was observed with Lp(a) 15-29.9 mg/dL (HR: 1.18; 95% CI 1.01-1.39) and Lp(a) ≥30 mg/dL (HR: 1.20; 95% CI 1.04-1.39), whereas such association was attenuated when hsCRP was <2 mg/L with Lp(a) 15-29.9 mg/dL (HR: 0.94; 95% CI 0.80-1.10) and Lp(a) ≥30 mg/dL (HR: 1.12; 95% CI 0.98-1.28). Moreover, when Lp(a) and hsCRP were combined for risk stratification, patients with dual elevation of these two biomarkers had a significant higher risk of MACCE compared with the reference group (Lp(a) < 15 mg/dL and hsCRp<2 mg/L) (p<0.05). CONCLUSIONS: In patients with CAD undergoing PCI, high Lp(a) level was associated with worse outcomes, and this association might be stronger in those with elevated hsCRP concomitantly. Evaluation of Lp(a) and hsCRP together may help identify high-risk individuals for targeted intervention in clinical utility.

Uncertainty and sensitivity analysis of radionuclide migration through fractured granite aquifer.

The radionuclide migration in the high-level radioactive waste (HLW) disposal is usually predicted by numerical simulations for risk analysis of radionuclide contamination in a large scale of time and space. However, the uncertainties in radionuclide migration models and their associated parameters significantly affect the simulation results. In the present study, we first selected certain parameters and output data as independent parameters and risk metrics and performed a series of radionuclide transport models at a research site in Northwestern China. The models considered radionuclide migration in the equivalent porous medium with the mechanism of nuclide decay in an arbitrary-length decay chain, adsorption, advection, diffusion, and dispersion. Then 3000 Monte Carlo (MC) simulations were performed to carry out a set of uncertainty and global sensitivity analysis by coupling an uncertainty quantification tool with a radionuclide migration simulator. The results indicated that both hydraulic gradient and hydraulic conductivity significantly influenced the risk metrics. Thus, it is critical to obtain hydraulic gradient and hydraulic conductivity data under the same economic conditions. We applied the multivariate adaptive regression spline (MARS) method to generate response surface models representing the relationships among independent parameters and risk metrics. Calculations of the risk metric distribution ranges revealed that the peak release doses would appear at 0.40 and 0.79 million years, and their values will be in the range of 4.7 × 10-7-1.93 × 10-6 Sv/a. Uncertainty and sensitivity analysis results of radionuclide contamination in the fractured granite upon which HLW is disposed can improve simulation and prediction accuracy for radionuclide migration.

Big Endothelin-1 and long-term all-cause death in patients with coronary artery disease and prediabetes or diabetes after percutaneous coronary intervention.

BACKGROUND AND AIMS: The present study aimed to examine the association between big endothelin-1 (big ET-1) and long-term all-cause death in patients with coronary artery disease (CAD) and different glucose metabolism status. METHODS AND RESULTS: We consecutively enrolled 8550 patients from January 2013 to December 2013. Patients were categorized according to both status of glucose metabolism status [Diabetes Mellitus (DM), Pre-Diabetes (Pre-DM), Normoglycemia (NG)] and big ET-1 levels. Primary endpoint was all-cause death. During a median of 5.1-year follow-up periods, 301 all-cause deaths occurred. Elevated big ET-1 was significantly associated with long-term all-cause death (adjusted HR: 2.230, 95%CI 1.629-3.051; p < 0.001). Similarly, patients with DM, but not Pre-DM, had increased risk of all-cause death compared with NG group (p < 0.05). When patients were categorized by both status of glucose metabolism and big ET-1 levels, high big ET-1 were associated with significantly higher risk of all-cause death in Pre-DM (adjusted HR: 2.442, 95% CI 1.039-5.740; p = 0.041) and DM (adjusted HR: 3.162, 95% CI 1.376-7.269; p = 0.007). The Kaplan-Meier curve indicated that DM patients with the highest big ET-1 levels were associated with the greatest risk of all-cause death (p < 0.05). CONCLUSIONS: The present data indicate that baseline big ET-1 levels were independently associated with the long-term all-cause death in DM and Pre-DM patients with CAD undergoing PCI, suggesting that big ET-1 may be a valuable marker in patients with impaired glucose metabolism.

Long-term effects of baseline on-treatment platelet reactivity in patients with acute coronary syndrome and thrombocytopenia undergoing percutaneous coronary intervention.

OBJECTIVE: To analyse the association between on-treatment platelet reactivity (TPR) and long-term outcomes of patients with acute coronary syndrome (ACS) and thrombocytopenia (TP) in the real world. METHODS: This prospective observational study enrolled patients with coronary artery disease (CAD) that underwent percutaneous coronary intervention (PCI). Patients with ACS and TP under dual antiplatelet therapy were selected for analysis. The 2- and 5-year clinical outcomes were evaluated among patients with high on-treatment platelet reactivity (HTPR), low on-treatment platelet reactivity (LTPR) and normal on-treatment platelet reactivity (NTPR), as tested by thromboelastogram at baseline. RESULTS: A total of 10 724 patients with CAD that underwent PCI were identified. Of these, 474 patients with ACS and TP met the inclusion criteria: 124 (26.2%) with HTPR, 163 (34.4%) with LTPR and 187 (39.5%) with NTPR. The 5-year rates of all-cause death, major adverse cardiovascular and cerebrovascular events, cardiac death, myocardial infarction, revascularization, stroke and bleeding were not significantly different among the three groups. Multivariate Cox regression analysis demonstrated that patients with HTPR were not independently associated with any of the 5-year endpoints compared with patients with NTPR. CONCLUSIONS: TPR at baseline was not independently associated with long-term outcomes in patients with ACS and TP that underwent PCI.

Platelet P2Y12 inhibiting therapy in adjunct to vascular dose of rivaroxaban or aspirin: a pharmacodynamic study of dual pathway inhibition vs. dual antiplatelet therapy.

AIMS: Dual pathway inhibition (DPI) by adding a vascular dose of rivaroxaban to a single antiplatelet agent has emerged as a promising antithrombotic strategy. However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data on a P2Y12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) are limited. METHODS AND RESULTS: This investigation was a substudy analysis conducted in selected cohorts of patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamic (PD) study. We analysed data from 40 patients treated with either clopidogrel- or ticagrelor-based DAPT first, and clopidogrel- or ticagrelor-based DPI thereafter. PD measures explored key pathways involved in thrombus formation and included markers of (1) P2Y12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) thrombin receptor-activating peptide (TRAP)-induced platelet aggregation, (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. Compared with DAPT, on a background of the same P2Y12 inhibitor (clopidogrel or ticagrelor), DPI was associated with reduced thrombin generation, increased markers of cyclooxygenase-1 activity and TRAP-induced platelet aggregation, and no differences in markers of P2Y12 signalling, platelet-mediated global thrombogenicity, and TF-induced platelet aggregation. In an analysis according to P2Y12 inhibitor type, ticagrelor reduced markers of platelet-mediated global thrombogenicity, P2Y12 signalling, and rates of high platelet reactivity compared with clopidogrel. CONCLUSION: Compared with DAPT with aspirin and a P2Y12 inhibitor, the use of a P2Y12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03718429.

High fibrinogen-to-albumin ratio with type 2 diabetes mellitus is associated with poor prognosis in patients undergoing percutaneous coronary intervention: 5-year findings from a large cohort.

BACKGROUND: Inflammation plays a crucial role in coronary atherosclerosis progression, and growing evidence has demonstrated that the fibrinogen-to-albumin ratio (FAR), as a novel inflammation biomarker, is associated with the severity of coronary artery disease (CAD). However, the long-term risk of cardiovascular events remains indistinct in patients with different level of FAR and different glycemic metabolism status. This study was to assess 5-year clinical outcomes of diabetic and non-diabetic patients who underwent percutaneous coronary intervention (PCI) with different level of FAR. METHODS: We consecutively enrolled 10,724 patients with CAD hospitalized for PCI and followed up for the major adverse cardiac and cerebrovascular events (MACCE) covering all-cause mortality, cardiac mortality, non-fatal myocardial infarction, non-fatal ischemic stroke, and unplanned coronary revascularization. FAR was computed using the following formula: Fibrinogen (g/L)/Albumin (g/L). According to the optimal cut-off value of FAR for MACCE prediction, patients were divided into higher level of FAR (FAR-H) and lower level of FAR (FAR-L) subgroups, and were further categorized into four groups as FAR-H with DM and non-DM, and FAR-L with DM and non-DM. RESULTS: 5298 patients (58.36 ± 10.36 years, 77.7% male) were ultimately enrolled in the present study. A total of 1099 (20.7%) MACCEs were documented during the 5-year follow-up. The optimal cut-off value of FAR was 0.0783 by the surv_cutpoint function. Compared to ones with FAR-H and DM, patients with FAR-L and non-DM, FAR-H and non-DM, FAR-L and DM had decreased risk of MACCEs [adjusted hazard ratio (HR): 0.75, 95% confidence interval (CI) 0.64-0.89, P = 0.001; HR: 0.78, 95% CI 0.66-0.93, P = 0.006; HR: 0.81, 95% CI 0.68-0.97, P = 0.019; respectively]. Notably, non-diabetic patients with lower level of FAR also had lower all-cause mortality and cardiac mortality risk than those in the FAR-H/DM group (HR: 0.41, 95% CI 0.27-0.63, P < 0.001; HR: 0.30, 95% CI 0.17-0.53, P < 0.001; respectively). Multivariate Cox proportional hazards regression analysis also indicated the highest risk of MACCEs in patients with FAR-H and DM than others (P for trend = 0.005). In addition, post-hoc analysis revealed consistent effects on 5-year MACCE across various subgroups. CONCLUSION: In this real-world cohort study, higher level of FAR combined with DM was associated with worse 5-year outcomes among patients with CAD undergoing PCI. The level of FAR may help to identify high-risk individuals in this specific population, where more precise risk assessment should be performed.

Pharmacodynamic Profiles of Dual-Pathway Inhibition with or without Clopidogrel versus Dual Antiplatelet Therapy in Patients with Atherosclerotic Disease.

AIM: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy and how it compares to standard dual antiplatelet therapy (DAPT). METHODS AND RESULTS: This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease-enrolled within a larger prospective, open-label, parallel-group PD study-who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI), or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF (collagen-related peptide + adenosine diphosphate [ADP] + tissue factor [TF]), markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and thrombin receptor-activating peptide [TRAP]), thrombin generation, and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend toward reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP-induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase-1-mediated activity. CONCLUSION: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations suggest that modulating thrombin generation-by means of factor Xa inhibition-in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of a DPI strategy observed in clinical trials.

Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic effects of ticagrelor in patients with diabetes mellitus and coronary artery disease.

AIMS: Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown. METHODS AND RESULTS: In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients. CONCLUSION: In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov Unique Identifier: NCT02539160.

Does Prior Stroke Predict Long-Term Recurrent Stroke After Percutaneous Coronary Intervention? Five-Year Results From a Large Cohort Study.

Background: We found a positive correlation between the prior stroke history and recurrent stroke in patients who underwent percutaneous coronary intervention (PCI) in our previous study, which indicated the close interaction of stroke and cardiovascular diseases. However, it is unclear whether prior stroke is still associated with worse prognosis at a longer follow-up period. Methods: A total of 10,724 coronary heart disease (CHD) patients who received PCI from January to December 2013 were prospectively enrolled and were subsequently divided into the prior stroke (n = 1,150) and non-prior stroke (n = 9,574) groups according to their history. Baseline characteristics and 5-year outcomes were recorded. Results: Patients with prior stroke had more clinical risk factors, as well as more extensive coronary artery lesions. Although in-hospital outcomes were similar between patients from the two groups, the 5-year follow-up result revealed that patients with prior stroke experienced higher incidence of stroke, major adverse cardiac and cerebrovascular events (MACCEs), all-cause death, and cardiac death (7.0 vs. 3.0%, p < 0.001; 25.9 vs. 20.3%, p < 0.001; 5.3 vs. 3.5%, p = 0.002; 3.1 vs. 2.1%, p = 0.032, respectively). After the propensity score matching, the 5-year stroke rate was still higher in the prior stroke group (6.8 vs. 3.4%, p = 0.001). The multivariable regression analysis also identified the prior stroke as a risk predictor of the 5-year stroke (HR = 2.011, 95% CI: 1.322-3.059, p = 0.001). Conclusions: Coronary heart disease patients with prior stroke who received PCI had a higher incidence of 5-year long-term adverse cardiovascular and cerebrovascular events, especially recurrent stroke. Prior stroke was a strong risk predictor of future stroke events.

5-Year Clinical Outcomes of Successful Recanalisation for Coronary Chronic Total Occlusions in Patients With or Without Type 2 Diabetes Mellitus.

Background: Despite substantial improvement in chronic total occlusions (CTO) revascularization technique, the long-term clinical outcomes in diabetic patients with revascularized CTO remain controversial. Our study aimed to investigate the 5-year cardiovascular survival for patients with or without type 2 diabetes mellitus (DM) who underwent successful percutaneous coronary intervention (PCI) for CTO. Methods: Data of the current analysis derived from a large single-center, prospective and observational cohort study, including 10,724 patients who underwent PCI in 2013 at Fuwai Hospital. Baseline, angiographic and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which consisted of death, recurrent myocardial infarction (MI), stroke and target vessel revascularization (TVR). The secondary endpoint was all-cause mortality. Cox regression analysis and propensity-score matching was performed to balance the baseline confounders. Results: A total of 719 consecutive patients with ≥1 successful CTO-PCI were stratified into diabetic (n = 316, 43.9%) and non-diabetic (n = 403, 56.1%) group. During a median follow-up of 5 years, the risk of MACCE (adjusted hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.08-2.00, P = 0.013) was significantly higher in the diabetic group than in the non-diabetic group, whereas the adjusted risk of all-cause mortality (HR 2.37, 95% CI 0.94-5.98, P = 0.068) was similar. In the propensity score matched population, there were no significant differences in the risk of MACCE (HR 1.27, 95% CI 0.92-1.75, P = 0.155) and all-cause mortality (HR 2.56, 95% CI 0.91-7.24, P = 0.076) between groups. Subgroup analysis and stratification analysis revealed consistent effects on 5-year MACCE across various subgroups. Conclusions: In patients who received successful CTO-PCI, non-diabetic patients were related to better long-term survival benefit in terms of MACCE. The risk of 5-year MACCE appeared to be similar in less-controlled and controlled diabetic patients after successful recanalization of CTO. Further randomized studies are warranted to confirm these findings.

Prognostic value of fibrinogen in patients with coronary artery disease and prediabetes or diabetes following percutaneous coronary intervention: 5-year findings from a large cohort study.

BACKGROUND: Fibrinogen (FIB) is an independent risk factor for mortality and cardiovascular events in the general population. However, the relationship between FIB and long-term mortality among CAD patients undergoing PCI remains unclear, especially in individuals complicated with diabetes mellitus (DM) or prediabetes (Pre-DM). METHODS: 6,140 patients with CAD undergoing PCI were included in the study and subsequently divided into three groups according to FIB levels (FIB-L, FIB-M, FIB-H). These patients were further grouped by glycemic status [normoglycemia (NG), Pre-DM, DM]. The primary endpoint was all-cause mortality. The secondary endpoint was cardiac mortality. RESULTS: FIB was positively associated with hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) in CAD patients with and without DM (P < 0.001). During a median follow-up of 5.1 years (interquartile range 5.0-5.2 years), elevated FIB was significantly associated with long-term all-cause mortality (adjusted HR: 1.86; 95% CI 1.28-2.69; P = 0.001) and cardiac mortality (adjusted HR: 1.82; 95% CI 1.15-2.89; P = 0.011). Similarly, patients with DM, but not Pre-DM, had increased risk of all-cause and cardiac mortality compared with NG group (all P < 0.05). When grouped by both FIB levels and glycemic status, diabetic patients with medium and high FIB levels had higher risk of mortality [(adjusted HR: 2.57; 95% CI 1.12-5.89), (adjusted HR: 3.04; 95% CI 1.35-6.82), all P < 0.05]. Notably, prediabetic patients with high FIB also had higher mortality risk (adjusted HR: 2.27; 95% CI 1.01-5.12). CONCLUSIONS: FIB was independently associated with long-term all-cause and cardiac mortality among CAD patients undergoing PCI, especially in those with DM and Pre-DM. FIB test may help to identify high-risk individuals in this specific population.